PROJECT SUMMARY - Drug Discovery and Development Core (Core B) The Drug Discovery and Development (DDD) Core is a closed core that will support contraceptive development research projects 1-3 of this interdisciplinary U54 center with the expertise to discover and develop male contraceptive agents. The DDD Core will develop a BRDT tandem screen (project 2), ATP-competitive kinase inhibitor and allosteric inhibitor assays for TSSK6 (project 3), and perform high throughput screens with 100,000 compounds for both projects 2 and 3. Screening hits will be prioritized computationally and confirmed using biochemical, biophysical, and analytical chemistry methods. Additionally, the DDD Core will support projects 1-3 with protein production, crystallography, and biophysical and biochemical characterization. Purified proteins will be co-crystallized with small molecules and the structures of the molecular complexes will be determined at atomic resolution. The resultant structural data will be used for in silico screening and will be combined with biochemical and biophysical data for rational, structure-based drug design to drive lead optimization. The DDD Core will support projects 1-3 by optimizing screening hits and leads using an iterative medicinal chemistry approach. Leads will be optimized for potency, selectivity, and drug-like properties using structure- based drug design and the results from the binding, functional, and ADMET assays. Optimized lead compounds will be provided in quantities needed for animal studies. Pharmacokinetic studies will also be performed in the DDD Core to support the medicinal chemistry studies. The core will provide optimized leads to the projects for in vivo assessment of reversible induction of sterility in preparation for contraception trials and preclinical development. The optimized lead compounds may have the potential to enter human clinical trials with the ultimate goal of commercializing them for male contraception.